Polyene macrolides are a class of antifungal antibiotics which show a broad spectrum of activity in man against fungi and yeast pathogens. This is especially true of amphotericine B (AmB), which is an antifungal agent with a broad spectrum of fungistatic and fungicidal activity: Candida albicans, Coccidioides immitis, Sporotrichum, Cryptococcus neoformans, Histoplasma, Blastomyces, Rhizopus orizae, Aspergillus niger, etc. Despite the introduction of imidazoles, they still remain the most efficient drug against quite a number of conditions.
Furthermore, AmB has immunomodulating properties in mice and, to a certain degree, in man. It also enhances the activity of a certain number of anti-cancer drugs.
However, due to its macrocyclic nature and amphoteric character, the AmB which corresponds to the formula A below: ##STR1## is sparingly soluble in water and tends to form micelles in aqueous solution. Moreover, the toxicity of AmB towards animal cells and in particular kidney cells, lymphocytes and erythrocytes, imposes extreme precautions when using it clinically. This is especially the case for the treatment of deep-seated and systemic mycoses which have to be treated by intravenous administration.
These considerations have led many researchers to search for non-toxic and more soluble derivatives. Accordingly, a large number of derivatives have been produced which are modified either at the level of the acid function on C16 or at the level of the primary amine function on C3'. The work of the following authors may be mentioned in particular:
BRUZZESE et al., J. Pharm. sci. (1975), 64, 462: esterification of the carboxyl group; PA0 FALKOWSKI et al., German Patent No. 3,013,631: amidation of the carboxyl group; PA0 WRIGHT, U.S. Pat. No. 4,272,525: esterification of the carboxyl group and substitution of the amine on C3' by aminated acids; PA0 SCHAFFNER and BOROWSKI Antib. & Chemo. (1961), II, 724: acetylation of the amine; PA0 SIPOS and KESELSKI, U.S. Pat. No. 4,235,993: substitution of the amine group by a benzyl group; PA0 KULBAKH et al., U.S. Pat. No. 4,007,166: formation of an N-methyl-D-glucaminemacrolide complex; PA0 FALKOWSKI et al., U.S. Pat. No. 4,195,172, British Patent No. 1,387,187: reaction of glycol with the amine group.
Attempts have also been made to increase the solubility of amphotericine B by adding surface-active agents or by forming salts (European Patent 31,722). Unfortunately, all these attempts have resulted in derivatives which are unstable in solution or in derivatives which have lost their antibiotic properties.